tbuckley/cabot-search huggingface dataset:
NIMG-79. SPATIALLY MAPPED PREDICTIONS OF EVOLVING TUMOR RESPONSE OF HIGH-GRADE GLIOMA VIA IMAGE-DRIVEN MATHEMATICAL MODELING
Authors: Maguy Farhat, David Hormuth, Holly Langshaw, Juliana Bronk, Brandon Curl, Divya Yadav, Rituraj Upadhyay, Andrew Elliot, Jodi Goldman, Lily Erickson, Wasif Talpur, Maggie Lee, Thomas Yankeelov, Caroline Chung
Journal: Neuro-Oncology (2022)

Abstract Timely treatment response assessment of high-grade gliomas (HGG), crucial for driving therapeutic decisions, remains a challenge; as HGGs exhibit variable response to treatment within different sub-regions. Current assessment using multi-parametric MRI (mpMRI) depends largely upon follow-up (FU) imaging timepoints for achieving diagnostic certainty, which delays therapeutic interventions. Mathematical modeling (MM) of tumor growth and treatment response can provide spatiotemporal information of HGG evolution in response to treatment, thus allowing for prospective early identification of resilient tumor subregions. AIMS: We aim to initialize and calibrate an image-driven MM framework to forecast HGG response, both at the end of chemoradiotherapy (CRT) and at 3-month FU. METHODS In a prospective clinical study, weekly mpMRIs (post-contrast T1, T2 FLAIR, and diffusion) for patients with HGG receiving CRT were used to describe tumor extent and cellularity. This data collected from baseline (pre-CRT) till week 3 (mid-CRT) was used to calibrate a model family to forecast HGG response for each individual patient at week 6 (end CRT) and at 3-month FU. RESULTS Error between the forecasted and observed responses was assessed globally using percent error in tumor volume, and at the local level by Pearson correlation coefficient (PCC). In an initial cohort of 11 patients, our MM framework predictions had a percent error in tumor volume of less than 8.6% and at week 6 RT and less than 20% at 3 months FU. The PCCs were 0.84 at week 6 RT and 0.72 at 3 months FU. CONCLUSIONS Temporal consistency across this early evaluation of the model predictions show promise of image-driven MM for HGG response forecasting to guide timely personalized assessment and adjustment of treatment.
NCOG-13. BEVACIZUMAB IN IDH WILD TYPE ADULT PATIENTS WITH RECURRENT GLIOBLASTOMA: A REAL WORD STUDY IN CHINA
Authors: Run Cui, Chengcheng Guo, Qunying Yang, Yonggao Mou
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE To investigate the efficacy, safety and application mode of bevacizumab in IDH wild-type adult patients with relapsed GBM. METHODS The clinical data of IDH wild-type adult patients with recurrent GBM who received bevacizumab monotherapy or combined chemotherapy in Sun Yat-sen University Cancer Center from 2011 to 2020 were retrospectively analyzed. The enrolled patients had recurred for the first time or multiple times after received surgery, radiotherapy and temozolomide. The objective curative effect was evaluated according to the evaluation criteria of response assessment in neuro-oncology(RANO). Kaplan-Meier method was used for survival analysis, Log-Rank test and Cox regression model were used for prognosis analysis. Adverse reactions were evaluated according to CTC 5.0 standard. RESULTS 81 patients were enrolled, the objective response rate was 62.9%, the disease control rate was 80.2%, the median progression-free survival (PFS) was 4.4 months (95%CI: 4.0-4.8), and the median overall survival (OS) was 7.8 months (95%CI: 6.8-8.8). Univariate analysis showed that the number of recurrences, the dose of bevacizumab, and whether combined with chemotherapy had no effects on OS. Patients with disseminated tumors, KPS score ≥ 60, MGMT promoter methylation, and ki-67 &amp;lt; 30% had prolonged OS. Multivariate analysis showed that KPS score and MGMT promoter status were independent prognostic factors affecting OS. Major adverse events were mostly grade 1 to 2, including: myelosuppression, hypertension, elevated transaminases, nausea/vomiting, and constipation. No grade 4-5 adverse events occurred. CONCLUSION Bevacizumab therapy can improve the survival of IDH wild type adult patients with recurrent GBM and was well tolerated. Early or delayed use of bevacizumab after relapse, low-dose or high-dose usage, and whether combined with chemotherapy had no effect on the OS of patients. KPS score and MGMT methylation status were independent prognostic factors affecting OS.
TMIC-51. SEX-SPECIFIC T CELL BEHAVIOR DRIVES DIFFERENTIAL IMMUNE RESPONSES IN GLIOBLASTOMA
Authors: Juyeun Lee, Chaim Sneiderman, Gary Kohanbash, Naseer Sangwan, Justin Lathia
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor and shows poor outcomes as a median survival is 12-18 months with current standard-of-care of therapy. GBM exhibits sex differences in incidence and overall survival, with males experiencing a higher incidence and a worse prognosis compared to females. However, the role of immune cells in GBM sex differences outside of myeloid cells remains poorly understood. Using a syngeneic mouse GBM model, we recapitulated the sex differences observed in patients, with shortened survival in male hosts compared to female hosts. These findings were not recapitulated in immuno-deficient mouse strains such as NSG and RAG1KO mice, suggesting a role for immune system, specifically T cells, in GBM sex differences. Flow cytometry analysis of tumor-infiltrating leukocytes revealed that more T cells were found in female tumors, whereas male tumors were enriched in macrophages. Additionally, more T cells in male tumors exhibited high levels of inhibitory receptors, whereas most female T cells were more functional as measured by expression of anti-tumor cytokines such as TNF, IFN-gamma, and granzyme B. A bone marrow chimera model (BMC) revealed that male T cells retained their phenotype in female hosts, whereas female T cell behavior was affected by the male environment. Yet survival analysis on BMC model and adoptive transfer model suggests strong immune cell-intrinsic effect on controlling tumor progression, further supported by in vitro T cell exhaustion model. Lastly, we found that males have more progenitor exhausted T cells, which led to better response to anti-PD1 treatment. Collectively, these results suggest that both cell-intrinsic and cell-extrinsic factors regulate T cell activity in a sex-specific manner, providing insights to develop sex-specific therapeutic approaches.
EXTH-40. DIPGS SUPPRESS THE EFFICACY OF T CELL THERAPIES THROUGH DYSFUNCTIONAL IMMUNE SYNAPSE FORMATION
Authors: Jorge Ibanez, Haley Houke, Abdul Elayan, Jennifer Ocasio-Adorno, Nikhil Hebbar, Paulina Velasquez, Suzanne Baker, Giedre Krenciute
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal pediatric brain tumors. Thus, there is an urgent need for novel therapeutics. While chimeric antigen receptor (CAR) T-cell therapy has the potential to meet this need and early phase clinical studies with CAR T cells have shown safety and some efficacy, additional studies are needed to understand the lack of efficacy of CAR T cells against DIPGs. The goal of this study was to identify CAR T cell efficacy limiting factors in DIPG setting. To study that, we focused on targeting GRP78, an endoplasmic reticulum chaperone protein that is broadly expressed on the cell surface of DIPGs. We generated GRP78-specific CAR T cells and compared their effector function against U87 glioma and the patient-derived DIPG007 cell line. Despite that GRP78-CAR T cells recognize and kill U87 and DIPG007 tumor cells in vitro, they were only effective against U87 in vivo. In addition, in vitro cytokine production and T cell proliferation were heavily diminished in DIPG007, compared to U87. For full activation, T cells require a cell-to-cell interaction and the formation of a highly organized structure called immune synapse (IS). Experiments using confocal microscopy showed that the IS quality, measured as lytic granule accumulation and cytoskeleton organization at the IS, was impaired in DIPG007 when compared to U87. This dysfunctional IS correlated with poor T cell activation (calcium flux) as determined by live cell imaging. We observed the same dysfunctional IS formation regardless of CAR T cell specificity and targeted antigen expression level, indicating that the suppressive effect is DIPG tumor mediated. In summary, we demonstrate that DIPGs suppress CAR T cell effector function through dysfunctional IS formation. We are now testing genetic engineering approaches directed at improving IS formation to overcome the suppressive effects of DIPGs.
DNAR-15. POLYMORPHISM AT P21 CODON 31 PROVIDED A PREDICTION FOR BEVACIZUMAB THERAPY IN GLIOBLASTOMA MULTIFORME
Authors: Wen-Yu Cheng, Chiung-Chyi Shen, Ming-Tsang Chiao
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is a common, malignant brain tumor. While it rarely metastasizes to distant organs, the diffuse invasion of glioma cells within the brain makes it difficult to resect. P21 (Waf-1) is a cyclin-dependent kinase inhibitor that plays an essential role in cell growth arrest, terminal differentiation, and apoptosis. Thus, the existence of natural variants of p21 could be linked to specific cancer. The purpose of this study was to identify the polymorphism variants of p21 codon 31 (Ser31Arg) and to explore its role in the therapy of glioblastoma multiforme. A total of unrelated 99 GBM subjects, were enrolled in the study, and genomic DNA was obtained from each tumor sample for genotyping. Genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism method (PCR-RFLP analysis. Odds ratios (Ors) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis. We found that among these GBM patients, the distribution of codon 31 polymorphisms was 20.2% for Serine homozygotes (Ser/Ser), 32.3% for arginine homozygotes (Arg/Arg), and 47.5% for Serine/arginine heterozygotes (Ser/Arg). Although the polymorphisms of p21 codon 31 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Ser genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone. Our findings suggest that the p21 Ser31Arg polymorphism may play an important role in the pathogenesis and initiation of GBM. Moreover, the polymorphism seems to contribute to a significant prediction at early diagnosis for bevacizumab therapy.
NIMG-21. INTERIM ANALYSIS OF A PHASE II STUDY OF MULTIPARAMETRIC MR-GUIDED HIGH-DOSE RESPONSE-ADAPTIVE RADIOTHERAPY WITH CONCURRENT TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Michelle Kim, Madhava Aryal, Benjamin Rosen, Hemant Parmar, Daekeun You, Larry Junck, Denise Leung, Yoshie Umemura, Jason Heth, Wajd Al-Holou, Todd Hollon, Daniel Wahl, Theodore Lawrence, Yue Cao
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Biologically-informed radiotherapy (RT) targeting an adversely prognostic hypercellular/hyperperfused imaging phenotype in patients with newly diagnosed glioblastoma (GBM) may improve outcomes by identifying emerging regions of treatment resistance associated with survival (OS), and is under investigation in an ongoing Phase II trial (NCT04574856) of individualized, response-adaptive RT. METHODS In this single-arm phase II study, patients with newly diagnosed GBM following resection undergo dose-intensified chemoradiation targeting the residual hypercellular (TVHCV, mean contralateral normal brain+2SD) and hyperperfused tumor volume (TVCBV, contralateral normal frontal grey matter+1SD) identified using high b-value diffusion-weighted and dynamic contrast-enhanced perfusion MRI. The combination of TVHCVCBV (TVHCVCBV) is treated to 50 Gy in 20 fractions (2.5 Gy/fraction), and following mid-RT reassessment, the persistent and developing TVHCVCBV is treated to 30 Gy in 10 fractions (3 Gy/fraction). The primary endpoint is improvement in OS, with planned interim safety analysis. RESULTS Since October 2020, 16 of 30 patients have been enrolled. Median age was 58 years (range, 29-75) and 69% were male. No patient underwent biopsy only, and 50% had gross total resection; 23% had MGMT methylated tumors. Median TVHCV/TVCBV was 6.9 cc (range, 1.9-42.8) pre-RT and 30% (range, 1-72%) was nonenhancing. By mid-RT, TVHCVCBV was reduced to 4.2 cc (range, 0.8-34.3) and 47% (range, 3-74%) was nonenhancing. The TVHCVCBV persisting from pre- to mid-RT was 2.3 cc (range, 0-24.2), with an additional 1.8 cc (range, 0.3-20.6) newly developing outside the initial region. All patients underwent adaptive replanning for boost without interruption. Planned interim analysis determined an acceptable rate of neurologic toxicity and safety to continue enrollment. CONCLUSION Individualized, response adaptive RT using an advanced imaging biomarker to assess emerging and especially non-enhancing regions of treatment resistance in patients with GBM is feasible, with short term safety in an early cohort and longer-term efficacy outcomes anticipated with ongoing accrual.
EPCO-44. HOXD13 GENE PLAYS A ROLE AS A PUTATIVE MASTER EPIGENETIC REGULATOR IN GLIOMA RECURRENCE AND PROGRESSION
Authors: Natalia Morosini, Thais Sabedot, Simona Cazacu, Ana de Carvalho, Antonio Iavarone, Houtan Noushmehr
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Adult diffuse glioma is a heterogenous brain tumor group that has malignant potential and recurring properties. Glioma CpG island methylator phenotype (G-CIMP) associated with chromatin remodeling encompasses two different methylation degrees: G-CIMP-high and G-CIMP-low that have high levels of DNA methylation and loss of DNA methylation, respectively. G-CIMP-high confers a more favorable prognosis and better predictive values by altering transcriptional dynamics and the gene expression. METHODS We have performed Chromatin Immunoprecipitation Sequencing (ChIP-Seq) on DNA extracted from fresh frozen primary tumor tissues (G-CIMP-high and G-CIMP-low). We have processed the sequencing data by using FastQC (v.:0.11.5), bwa-mem (v.:0.7.15) and picard tool (v.:2.7.1). The ChIP-seq peaks and the differentially bound peaks were obtained using MACS2 (v.:2.1.1) and DiffBind (v.:3.4.11), respectively. We have also integrated transcriptomic, epigenomic and genomic data. RESULTS Initial results showed that the differentially bound H3K27ac and H3K4me3 peak gains and losses are located mainly in intronic and intergenic regions. The integration between epigenetic and transcriptomic data revealed that the promoter of the HOXD13 gene upregulated in GCIMP-low presents an active regulatory region and is enriched by H3K27ac and H3K4me3 sites. We were able to identify that GCIMP-low, in addition to presenting more downregulated genes than GCIMP-high, also has greater affinity to the H3K27ac peaks. In GCIMP-low, we identified that regions enriched by H3K27ac are highly associated with the presence H3K4me3 marks. CONCLUSION We mapped the enrichment of histone modifications in the TSS of differentially expressed genes in G-CIMP-high and G-CIMP-low identifying both the susceptibility of GIMP-low to interact with H3K27ac and the fact that the progression of GCIMP-high to G-CIMP-low can be explained by the association between H3K27ac gain and gene downregulation. Also, we predicted the HOXD13 gene as a putative master epigenetic regulator of the G-CIMP demethylation process and, consequently, of tumor recurrence and progression, over time.
PATH-35. HYPERMITOTIC MENINGIOMAS HARBOR DNA METHYLATION SUBGROUPS WITH DISTINCT BIOLOGICAL AND CLINICAL FEATURES
Authors: Abrar Choudhury, William Chen, Calixto-Hope Lucas, Stephen Magill, David Raleigh
Journal: Neuro-Oncology (2022)

Abstract Meningiomas are the most common primary intracranial tumors, and treatments for meningiomas are limited to surgery and radiotherapy. Clinically tractable biomarkers for meningiomas are under development, and multiple retrospective studies have reported genetic, epigenetic, or gene expression grouping schemes shedding light on meningioma biology, outcomes, or druggable dependencies. Here we report biologically distinct subgroups within the Hypermitotic meningioma DNA methylation group, validating an architecture that unifies contrasting theories of meningioma biology. To do so, we re-analyzed meningioma DNA methylation profiles from a discovery cohort (n=200) and an independent, consecutive validation cohort (n=365). Median follow-up was 5.6 years for 388/142/35 WHO grade 1/2/3 meningiomas. Copy number variants (CNVs) were calculated for all meningiomas, and RNA sequencing was performed on the discovery cohort. Unsupervised hierarchical clustering of β methylation values was performed on the discovery cohort, controlling for artifacts and inaccurate β methylation values due to the presence of CNVs. As previously reported, meningioma clustering was validated with the validation cohort and revealed 3 DNA methylation groups (Merlin-intact, Immune-enriched, or Hypermitotic) that were associated with distinct biological drivers, clinical outcomes, and therapeutic vulnerabilities. Further analysis using RNA sequencing revealed differential enrichment of FOXM1 target genes across 2 subgroups of Hypermitotic meningiomas. Gene expression programs in these subgroups were concordant with Proliferative or Hypermetabolic meningiomas reported by other investigators. Analysis of meningiomas by DNA methylation subgroup conserved biological features distinguishing DNA methylation groups, including CNVs deleting NF2, immune cell enrichment, or lymphatic gene expression. Analysis of clinical outcomes suggested subgroups may refine prediction of postoperative 5-year local freedom from recurrence (54.1% for Hypermetabolic vs 5.9% for Proliferative) or overall survival (82.2% for Hypermetabolic vs 21.8% for Proliferative) within DNA methylation groups. In summary, meningioma DNA methylation groups and the subgroups they harbor provide a framework unifying contrasting theories of meningioma biology.
CTIM-33. SEXUAL DIMORPHISM OF HUMAN IMMUNE SYSTEM PREDICTS CLINICAL OUTCOMES IN GLIOBLASTOMA IMMUNOTHERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Jack Shireman, Simon Ammanuel, Jens Eickhoff, Mahua Dey
Journal: Neuro-Oncology (2022)

Abstract Biological differences based on sex have been documented throughout scientific literature. Glioblastoma, the most common primary malignant brain tumor in adults, has a male sex incidence bias, however, no clinical trial data examining differential effects of treatment between sexes currently exist. We analyzed genomic data, as well as clinical trials, to delineate the effect of sex on the immune system and glioblastoma outcome following immunotherapy. We found that, in general females possess enriched immunological signatures on gene set enrichment analysis, that also stratified patient survival when delineated by sex. Female glioblastoma patients treated with immunotherapy had a statistically significant survival advantage at the 1-year compared to males (RR = 1.15; p = 0.0241). This effect was even more pronounced in vaccine-based immunotherapy, (RR = 1.29; p = 0.0158). Our study shows a meaningful difference in the immunobiology between males and females that also influences overall response to immunotherapy in the setting of glioblastoma. Our study adds to a growing body of literature examining sex differences in male and female immunology. We demonstrate both using large scale omic data sets, as well as clinical trials, that female sexually dimorphic genes are tied to immunological responses, and that females have better outcomes during GBM immunotherapy treatments. This data is critical to better inform treatment practices and further crystalizes the need for balanced trial design and prospective reporting of sex as a variable across all GBM clinical trials.
BIOM-07. LOW EXPRESSION OF HLA-A AS A NOVEL PROGNOSTIC FACTOR IN GLIOBLASTOMA TREATED WITH TUMOR FUSED DENDRITIC CELL VACCINES
Authors: Jun Takei, Yasuharu Akasaki, Toshihide Tanaka, Nei Fukasawa, Kazutaka Gomisawa, Mari Satake, Ryosuke Mori, Yohei Yamamoto, Ayaka Oda, Yuko Kamata, Mutsunori Murahashi, Takahiro Fukuda, Masayuki Shimoda, Yuichi Murayama
Journal: Neuro-Oncology (2022)

Abstract Although immunotherapy has become an attractive approach to cancer treatment in patients with broad types of aggressive tumors, phase III clinical trials of immunotherapy for glioblastoma (GBM) have not achieved extended survival of patients. Dendritic cells perform an essential role in the immune system as antigen-presenting cells and tumor fused dendritic cells (TFDCs) can induce tumor-specific cytotoxic T cells as a cancer vaccine. We have previously described the safety and mechanisms of TFDCs therapy, as well as immunological and clinical responses of patients with GBM, however, there were little known about predictive and prognostic biomarkers specific to TFDCs therapy. In the present study, we investigated the whole transcriptome sequencing of tumor cells, and novel prognostic factors were identified through molecular profiling GBM treated with TFDCs immunotherapy. Fifty-three patients were eligible in this study and 28 samples from patients with newly diagnosed GBM IDH wild-type were included. Of these 28 samples, 15 high-quality RNA samples successfully extracted from tumors were analysed. The samples were divided into two groups based on the median patient's overall survival. Differential expression analyses and enrichment analysis between the two groups were carried out using CLC Genomics Workbench (QIAGEN), and Gene Ontologies (GO) were assigned. A total of 473 differentially expressed genes were detected including 327 enriched GO terms. Fifteen GO terms out of 327 GO terms represented the highest enrichment scores, revealed that five GO terms were associated with the major histocompatibility complex (MHC). The relationship among the MHC, immune-related genes, and clinical outcomes was investigated using the Cox regression model and Kaplan–Meier log-rank test. Low expression of HLA-A in the tumors turned out to be a significantly favorable prognostic impact (p = 0.01). The decreased expression of HLA-A might be a novel prognostic factor in GBM patients treated with TFDCs immunotherapy.